Objective: Aberrant expression of ten-eleven translocation 1 (TET1) plays a critical role in tumor development and progression. We systematically summarized the latest research progress on the role and mechanisms of TET1 in cancer biology.
Data Sources: Relevant articles published in English from 1980 to April 2016 were selected from the PubMed database. The terms “ten-eleven translocation 1,” “5mC,” “5hmC,” “microRNA,” “hypoxia,” and “embryonic stem cell” were used for the search.
Study Selection: Articles focusing on the role and mechanism of TET1 in tumor were reviewed, including clinical and basic research articles.
Results: TET proteins, the key enzymes converting 5-methylcytosine to 5-hydroxymethylcytosine, play vital roles in DNA demethylation regulation. Recent studies have shown that loss of TET1 is associated with tumorigenesis and can be used as a potential biomarker for cancer therapy, which indicates that TET1 serves as tumor suppressor gene. Moreover, besides its dioxygenase activity, TET1 could induce epithelial-mesenchymal transition and act as a coactivator to regulate gene transcription, such as developmental regulator in embryonic stem cells (ESCs) and hypoxia-responsive gene in cancer. The regulation of TET1 is also correlated with microRNA in a posttranscriptional modification process. Hence, it is complex but critical to comprehend the mechanisms of TET1 in the biology of ESCs and cancer.
Conclusions: TET1 not only serves as a demethylation enzyme but also plays multiple roles during tumorigenesis and progression. More studies should be carried out to elucidate the exact mechanisms of TET1 and its associations with cancer before considering it as a therapeutic tool.

Background: Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy (SAE) is still poorly understood. The aim of this prospective and observational study was to investigate the clinical significance of calcium-binding protein A8 (S100A8) in serum and tumor necrosis factor receptor-associated factor 6 (TRAF6) in peripheral blood mononuclear cells (PBMCs) in diagnosing SAE and predicting its prognosis.
Methods: Data of septic patients were collected within 24 h after Intensive Care Unit admission from July 2014 to March 2015. Healthy medical personnel served as the control group. SAE was defined as cerebral dysfunction in the presence of sepsis that fulfilled the exclusion criteria. The biochemical indicators, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation score II, TRAF6 in PBMC, serum S100A8, S100β, and neuron-specific enolase were evaluated in SAE patients afresh. TRAF6 and S100A8 were also measured in the control group.
Results: Of the 57 enrolled patients, 29 were diagnosed with SAE. The S100A8 and TRAF6 concentrations in SAE patients were both significantly higher than that in no-encephalopathy (NE) patients, and higher in NE than that in controls (3.74 ± 3.13 vs. 1.08 ± 0.75 vs. 0.37 ± 0.14 ng/ml, P < 0.01; 3.18 ± 1.55 vs. 1.02 ± 0.63 vs. 0.47 ± 0.10, P < 0.01). S100A8 levels of 1.93 ng/ml were diagnostic of SAE with 92.90% specificity and 69.00% sensitivity in the receiver operating characteristic (ROC) curve, and the area under the curve was 0.86 (95% confidence interval [CI]: 0.76–0.95). TRAF6-relative levels of 1.44 were diagnostic of SAE with 85.70% specificity and 86.20% sensitivity, and the area under the curve was 0.94 (95% CI: 0.88–0.99). In addition, S100A8 levels of 2.41 ng/ml predicted 28-day mortality of SAE with 90.00% specificity and 73.70% sensitivity in the ROC curve, and the area under the curve was 0.88. TRAF6 relative levels of 2.94 predicted 28-day mortality of SAE with 80.00% specificity and 68.40% sensitivity, and the area under the curve was 0.77. Compared with TRAF6, the specificity of serum S100A8 in diagnosing SAE and predicting mortality was higher, although the sensitivity was low. In contrast, the TRAF6 had higher sensitivity for diagnosis.
Conclusions: Peripheral blood levels of S100A8 and TRAF6 in SAE patients were elevated and might be related to the severity of SAE and predict the outcome of SAE. The efficacy and specificity of S100A8 for SAE diagnosis were superior, despite its weak sensitivity. S100A8 might be a better biomarker for diagnosis of SAE and predicting prognosis.

Background: An acute respiratory distress syndrome (ARDS) is still one of the major challenges in critically ill patients. This study aimed to investigate the effect of inhibiting c-Jun N-terminal kinase (JNK) on ARDS in a lipopolysaccharide (LPS)-induced ARDS rat model.
Methods: Thirty-six rats were randomized into three groups: control, LPS, and LPS + JNK inhibitor. Rats were sacrificed 8 h after LPS treatment. The lung edema was observed by measuring the wet-to-dry weight (W/D) ratio of the lung. The severity of pulmonary inflammation was observed by measuring myeloperoxidase (MPO) activity of lung tissue. Moreover, the neutrophils in bronchoalveolar lavage fluid (BALF) were counted to observe the airway inflammation. In addition, lung collagen accumulation was quantified by Sircol Collagen Assay. At the same time, the pulmonary histologic examination was performed, and lung injury score was achieved in all three groups.
Results: MPO activity in lung tissue was found increased in rats treated with LPS comparing with that in control (1.26 ± 0.15 U in LPS vs. 0.77 ± 0.27 U in control, P < 0.05). Inhibiting JNK attenuated LPS-induced MPO activity upregulation (0.52 ± 0.12 U in LPS + JNK inhibitor vs. 1.26 ± 0.15 U in LPS, P < 0.05). Neutrophils in BALF were also found to be increased with LPS treatment, and inhibiting JNK attenuated LPS-induced neutrophils increase in BALF (255.0 ± 164.4 in LPS vs. 53 (44.5-103) in control vs. 127.0 ± 44.3 in LPS + JNK inhibitor, P < 0.05). At the same time, the lung injury score showed a reduction in LPS + JNK inhibitor group comparing with that in LPS group (13.42 ± 4.82 vs. 7.00 ± 1.83, P = 0.001). However, the lung W/D ratio and the collagen in BALF did not show any differences between LPS and LPS + JNK inhibitor group.
Conclusions: Inhibiting JNK alleviated LPS-induced acute lung inflammation and had no effects on pulmonary edema and fibrosis. JNK inhibitor might be a potential therapeutic medication in ARDS, in the context of reducing lung inflammatory.

Background: There has been no external validation of survival prediction models for severe adult respiratory distress syndrome (ARDS) with extracorporeal membrane oxygenation (ECMO) therapy in China. The aim of study was to compare the performance of multiple models recently developed for patients with ARDS undergoing ECMO based on Chinese single-center data.
Methods: A retrospective case study was performed, including twenty-three severe ARDS patients who received ECMO from January 2009 to July 2015. The PRESERVE (Predicting death for severe ARDS on VV-ECMO), ECMOnet, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score, a center-specific model developed for inter-hospital transfers receiving ECMO, and the classical risk-prediction scores of Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) were calculated. In-hospital and six-month mortality were regarded as the endpoints and model performance was evaluated by comparing the area under the receiver operating characteristic curve (AUC).
Results: The RESP and APACHE II scores showed excellent discriminate performance in predicting survival with AUC of 0.835 (95% confidence interval [CI], 0.659–1.010, P = 0.007) and 0.762 (95% CI, 0.558–0.965, P = 0.035), respectively. The optimal cutoff values were risk class 3.5 for RESP and 35.5 for APACHE II score, and both showed 70.0% sensitivity and 84.6% specificity. The excellent performance of these models was also evident for the pneumonia etiological subgroup, for which the SOFA score was also shown to be predictive, with an AUC of 0.790 (95% CI, 0.571–1.009, P = 0.038). However, the ECMOnet and the score developed for externally retrieved ECMO patients failed to demonstrate significant discriminate power for the overall cohort. The PRESERVE model was unable to be evaluated fully since only one patient died six months postdischarge.
Conclusions: The RESP, APCHAE II, and SOFA scorings systems show good predictive value for intra-hospital survival of ARDS patients treated with ECMO in our single-center evaluation. Future validation should include a larger study with either more patients' data at single-center or by integration of domestic multi-center data. Development of a scoring system with national characteristics might be warranted.

Background: Early goal-directed therapy (EGDT) has become an important therapeutic management in early salvage stage of septic shock. However, splenic organs possibly remained hypoperfused and hypoxic despite fluid resuscitation. This study aimed to evaluate the effect of EGDT on hepatic perfusion in septic shock patients.
Methods: A prospective observational study was carried out in early septic shock patients who were admitted to Intensive Care Unit within 24 h after onset and who met all four elements of the EGDT criteria after treatment with the standard EGDT procedure within 6 h between December 1, 2012 and November 30, 2013. The hemodynamic data were recorded, and oxygen metabolism and hepatic functions were monitored. An indocyanine green clearance test was applied to detect the hepatic perfusion. The patients' characteristics were compared before treatment (T0), immediately after EGDT (T1), and 24 h after EGDT (T2). This study is registered at ClinicalTrials.org, NCT02060773.
Results: Twenty-one patients were included in the study; however, the hepatic perfusion data were not included in the analysis for two patients; therefore, 19 patients were eligible for the study. Hemodynamics data, as monitored by pulse-indicator continuous cardiac output, were obtained from 16 patients. There were no significant differences in indocyanine green plasma disappearance rate (ICG-PDR) and 15-min retention rate (R15) at T0 (11.9 ± 5.0%/min and 20.0 ± 13.2%), T1 (11.4 ± 5.1%/min and 23.6 ± 14.9%), and T2 (11.0 ± 4.5%/min and 23.7 ± 15.3%) (all P > 0.05). Both of the alterations of ICG-PDR and R15 showed no differences at T0, T1, and T2 in the patients of different subgroups that achieved different resuscitation goal numbers when elected (P > 0.05).
Conclusion: There were no hepatic perfusion improvements after EGDT in the early phase of patients with septic shock.
Trial Registration: Clinicaltrials.gov NCT02060773 (https://clinicaltrials.gov/ct2/show/NCT02060773).

Background: The expression of dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) in renal tubular epithelial cells has been thought to be highly correlated with the occurrence of several kidney diseases, but whether it takes place in renal tissues during hemorrhagic shock (HS) is unknown. The present study aimed to investigate this phenomenon and the inhibitory effect of Vitamin C (VitC).
Methods: A Sprague–Dawley rat HS model was established in vivo in this study. The expression level and location of DC-SIGN were observed in kidneys. Also, the degree of histological damage, the concentrations of tumor necrosis factor-μ and interleukin-6 in the renal tissues, and the serum concentration of blood urea nitrogen and creatinine at different times (2–24 h) after HS (six rats in each group), with or without VitC treatment before resuscitation, were evaluated.
Results: HS induced DC-SIGN expression in rat tubular epithelial cells. The proinflammatory cytokine concentration, histological damage scores, and functional injury of kidneys had increased. All these phenomena induced by HS were relieved when the rats were treated with VitC before resuscitation.
Conclusions: The results of the present study illustrated that HS could induce tubular epithelial cells expressing DC-SIGN, and the levels of proinflammatory cytokines in the kidney tissues improved correspondingly. The results also indicated that VitC could suppress the DC-SIGN expression in the tubular epithelial cells induced by HS and alleviate the inflammation and functional injury in the kidney.

Background: Over the years, the mechanical ventilation (MV) strategy has changed worldwide. The aim of the present study was to describe the ventilation practices, particularly lung-protective ventilation (LPV), among brain-injured patients in China.
Methods: This study was a multicenter, 1-day, cross-sectional study in 47 Intensive Care Units (ICUs) across China. Mechanically ventilated patients (18 years and older) with brain injury in a participating ICU during the time of the study, including traumatic brain injury, stroke, postoperation with intracranial tumor, hypoxic-ischemic encephalopathy, intracranial infection, and idiopathic epilepsy, were enrolled. Demographic data, primary diagnoses, indications for MV, MV modes and settings, and prognoses on the 60th day were collected. Multivariable logistic analysis was used to assess factors that might affect the use of LPV.
Results: A total of 104 patients were enrolled in the present study, 87 (83.7%) of whom were identified with severe brain injury based on a Glasgow Coma Scale ≤8 points. Synchronized intermittent mandatory ventilation (SIMV) was the most frequent ventilator mode, accounting for 46.2% of the entire cohort. The median tidal volume was set to 8.0 ml/kg (interquartile range [IQR], 7.0–8.9 ml/kg) of the predicted body weight; 50 (48.1%) patients received LPV. The median positive end-expiratory pressure (PEEP) was set to 5 cmH2O (IQR, 5–6 cmH2O). No PEEP values were higher than 10 cmH2O. Compared with partially mandatory ventilation, supportive and spontaneous ventilation practices were associated with LPV. There were no significant differences in mortality and MV duration between patients subjected to LPV and those were not.
Conclusions: Among brain-injured patients in China, SIMV was the most frequent ventilation mode. Nearly one-half of the brain-injured patients received LPV. Patients under supportive and spontaneous ventilation were more likely to receive LPV.
Trial Registration: ClinicalTrials.org NCT02517073 https://clinicaltrials.gov/ct2/show/NCT02517073.

Background: Inflammation is supposed to play a key role in the pathophysiological processes of intestinal ischemia-reperfusion injury (IIRI), and Candida albicans in human gut commonly elevates inflammatory cytokines in intestinal mucosa. This study aimed to explore the effect of C. albicans on IIRI.
Methods: Fifty female Wistar rats were divided into five groups according to the status of C. albicans infection and IIRI operation: group blank and sham; group blank and IIRI; group cefoperazone plus IIRI; group C. albicans plus cefoperazone and IIRI (CCI); and group C. albicans plus cefoperazone and sham. The levels of inflammatory factors tumor necrosis factor (TNF)-μ, interleukin (IL)-6, IL-1β, and diamine oxidase (DAO) measured by enzyme-linked immunosorbent assay were used to evaluate the inflammation reactivity as well as the integrity of small intestine. Histological scores were used to assess the mucosal damage, and the C. albicans blood translocation was detected to judge the permeability of intestinal mucosal barrier.
Results: The levels of inflammatory factors TNF-μ, IL-6, and IL-1β in serum and intestine were higher in rats undergone both C. albicans infection and IIRI operation compared with rats in other groups. The levels of DAO (serum: 44.13 ± 4.30 pg/ml, intestine: 346.21 ± 37.03 pg/g) and Chiu scores (3.41 ± 1.09) which reflected intestinal mucosal disruption were highest in group CCI after the operation. The number of C. albicans translocated into blood was most in group CCI ([33.80 ± 6.60] ×102 colony forming unit (CFU)/ml).
Conclusion: Intestinal C. albicans infection worsened the IIRI-induced disruption of intestinal mucosal barrier and facilitated the subsequent C. albicans translocation and dissemination.

Background: It is unclear that how to decide the calcium infusion rate during continuous veno-venous hemofiltration (CVVH) with regional citrate anticoagulation (RCA). This study aimed to assess the determinants of calcium infusion rate during CVVH with RCA in critically ill patients with acute kidney injury (AKI).
Methods: A total of 18 patients with AKI requiring CVVH were prospectively analyzed. Postdilution CVVH was performed with a fixed blood flow rate of 150 ml/min and a replacement fluid flow rate of 2000 ml/h for each new circuit. The infusion of 4% trisodium citrate was started at a rate of 29.9 mmol/h prefilter and adjusted according to postfilter ionized calcium. The infusion of 10% calcium gluconate was initiated at a rate of 5.5 mmol/h and adjusted according to systemic ionized calcium. The infusion rate of trisodium citrate and calcium gluconate as well as ultrafiltrate flow rate were recorded at 1, 2, 4, 6, 12, and 24 h after starting CVVH, respectively. The calcium loss rate by CVVH was also calculated.
Results: Fifty-seven sessions of CVVH were performed in 18 AKI patients. The citrate infusion rate, calcium loss rate by CVVH, and calcium infusion rate were 31.30 (interquartile range: 2.70), 4.60 ± 0.48, and 5.50 ± 0.35 mmol/h, respectively. The calcium infusion rate was significantly higher than that of calcium loss rate by CVVH (P < 0.01). The correlation coefficient between the calcium and citrate infusion rates, and calcium infusion and calcium loss rates by CVVH was −0.031 (P > 0.05) and 0.932 (P < 0.01), respectively. In addition, calcium infusion rate (mmol/h) = 1.77 + 0.8 × (calcium loss rate by CVVH, mmol/h).
Conclusions: The calcium infusion rate correlates significantly with the calcium loss rate by CVVH but not with the citrate infusion rate in a fixed blood flow rate during CVVH with RCA.

Background: Intact endothelial structure and function are critical for maintaining microcirculatory homeostasis. Dysfunction of the latter is an underlying cause of various organ pathologies. In a previous study, we showed that rhubarb, a traditional Chinese medicine, protected intestinal mucosal microvascular endothelial cells in rats with metastasizing septicemia. In this study, we investigated the effects and mechanisms of rhubarb on matrix metalloproteinase-9 (MMP9)-induced vascular endothelial (VE) permeability.
Methods: Rhubarb monomers were extracted and purified by a series of chromatography approaches. The identity of these monomers was analyzed by hydrogen-1 nuclear magnetic resonance (NMR), carbon-13 NMR, and distortionless enhancement by polarization transfer magnetic resonance spectroscopy. We established a human umbilical vein endothelial cell (HUVEC) monolayer on a Transwell insert. We measured the HUVEC permeability, proliferation, and the secretion of VE-cadherin into culture medium using fluorescein isothiocyanate-dextran assay, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, and enzyme-linked immunosorbent assay, respectively, in response to treatment with MMP9 and/or rhubarb monomers.
Results: A total of 21 rhubarb monomers were extracted and identified. MMP9 significantly increased the permeability of the HUVEC monolayer, which was significantly reduced by five individual rhubarb monomer (emodin, 3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid, 1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl)-β-D-glucose, daucosterol linoleate, and rhein) or a combination of all five monomers (1 μmol/L for each monomer). Mechanistically, the five-monomer mixture at 1 μmol/L promoted HUVEC proliferation. In addition, MMP9 stimulated the secretion of VE-cadherin into the culture medium, which was significantly inhibited by the five-monomer mixture.
Conclusions: The rhubarb mixture of emodin, 3,8-dihydroxy-1-methyl-anthraquinone-2-carboxylic acid, 1-O-caffeoyl-2-(4-hydroxyl-O-cinnamoyl)-β-D-glucose, daucosterol linoleate, and rhein, at a low concentration, antagonized the MMP9-induced HUVEC monolayer permeability by promoting HUVEC proliferation and reducing extracellular VE-cadherin concentrations.